Mucopolysaccharidosis I

MPS I

Mucopolysaccharidosis Type I (MPS I), also known as Hurler (severe MPS I), Scheie, and Hurler-Scheie (attenuated / less severe MPS I) syndrome is part of a group of rare lysosomal storage diseases (LSD) caused by reduced levels, or the complete lack of, an enzyme responsible for the catabolism (break down) of glycosaminoglycans (GAGs) and resulting in the progressive accumulation of GAGs in the tissue. 1

GAG accumulation has a direct effect on connective tissue formation and function, causing progressive cellular damage affecting multiple organ systems and can lead to organ failure, cognitive impairment and reduced life expectancy.1

People with severe MPS I typically have an earlier onset of symptoms, a decline in intellectual function, and without treatment individuals with severe MPS I typically die before 10 years of age.1

Attenuated MPS I typically has a later onset of symptoms, milder symptoms and slower disease progression. While individuals with attenuated MPS I may develop significant disease-related morbidity, they typically show normal intelligence and may survive into adulthood.1

Heart disease and airway obstruction are major causes of death in all people with MPS I.2

Current standard of care for MPS includes haematopoietic stem cell transplantation (HSCT) and/or disease modifying enzyme replacement therapy (ERT), or supportive medical and surgical interventions.3

Despite available therapies people with MPS diseases continue to experience bone and joint manifestations, chronic pain, and physical disability, which generally persist despite treatment with HSCT and ERT.3

MPS I is present in about 1 in every 100,000 live births.4

Mucopolysaccharidosis I

MPS I

Mucopolysaccharidosis Type I (MPS I), also known as Hurler (severe MPS I), Scheie, and Hurler-Scheie (attenuated / less severe MPS I) syndrome is part of a group of rare lysosomal storage diseases (LSD) caused by reduced levels, or the complete lack of, an enzyme responsible for the catabolism (break down) of glycosaminoglycans (GAGs) and resulting in the progressive accumulation of GAGs in the tissue. 1

GAG accumulation has a direct effect on connective tissue formation and function, causing progressive cellular damage affecting multiple organ systems and can lead to organ failure, cognitive impairment and reduced life expectancy.1

People with severe MPS I typically have an earlier onset of symptoms, a decline in intellectual function, and without treatment individuals with severe MPS I typically die before 10 years of age.1

Attenuated MPS I typically has a later onset of symptoms, milder symptoms and slower disease progression. While individuals with attenuated MPS I may develop significant disease-related morbidity, they typically show normal intelligence and may survive into adulthood.1

Heart disease and airway obstruction are major causes of death in all people with MPS I.2

Current standard of care for MPS includes haematopoietic stem cell transplantation (HSCT) and/or disease modifying enzyme replacement therapy (ERT), or supportive medical and surgical interventions.3

Despite available therapies people with MPS diseases continue to experience bone and joint manifestations, chronic pain, and physical disability, which generally persist despite treatment with HSCT and ERT.3

MPS I is present in about 1 in every 100,000 live births.4

Key MPS I Figures

Incidence of live births4
1/100K
Expected lifespan with severe form, untreated1
10 YRS
Expected lifespan with attenuated form1
50 YRS
Market size (USD/pa) by 20275
$828M+

Key MPS I Figures

Incidence of live births4
1/100K
Expected lifespan with severe form, untreated1
10 YRS
Expected lifespan with attenuated form1
50 YRS
Market size (USD/pa) by 20275
$828M+

Drug in development

Pentosan
Polysulfate
Sodium

for subcutaneous injection

Potential

There is an unmet need to help manage bone and joint manifestations, chronic pain, and physical disability, key clinical manifestations of MPS I which remain despite treatment with HSCT and ERT.3
PPS has been shown to reduce GAG levels, inflammatory biomarkers, joint stiffness, and pain in preclinical MPS models and in clinical trials in MPS patients.6-10

The mechanisms of action of PPS that are relevant to the treatment of MPS include:

- Reduction in systemic and accumulated GAGs in multiple tissues11
- Anti-inflammatory effects via the inhibition of NF-kB resulting in the reduction in pro-inflammatory mediators12
- Reduction of the expression of the pain mediator, nerve growth factor (NGF) in osteocytes from degenerating joints 13
- An ability to inhibit the cartilage degrading enzymes that are related to joint dysfunction observed in MPS14

Remodelling
Inflammation
Pain
Cartilage Loss

Development milestones

In 2018, Paradigm entered into an exclusive license agreement for the use of PPS to treat lysosomal storage diseases (LSDs) including MPS (MPS types I, II, III, IV, VI and VII), Gaucher and Fabry diseases. The licensing agreement is a valuable addition to Paradigm’s product pipelines and IP portfolio. Granted patents cover key regions such as USA, Japan, Europe, Australia and New Zealand.

In addition, Paradigm has an exclusive supply and license agreement with the only FDA approved PPS supplier, bene pharmaChem, extending for 25 years post registration.

Paradigm’s current focus is on MPS Types I and VI, where there is an unmet medical need to manage residual musculoskeletal and pain symptoms.

Paradigm has received Orphan Designations in both the USA and EU for MPS Types I and VI. These designations allow for faster processing times for clinical trials in these regions, more regulatory support from the EMA, and for longer market exclusivity periods in the US and EU.

Considering the encouraging results of PPS effect on pain, function and biomarkers seen in animals and clinical studies reported to date, and the support of global leaders in MPS, Paradigm has commenced a clinical program assessing subcutaneous (SC) injections of PPS in MPS I.

In 2020 Paradigm commenced an open‐label single‐centre pilot study in up to 10 patients assessing SC injections of PPS in participants with MPS I who have received ERT and/or HSCT. (PARA_MPSI_001)

The primary objective of the study is to evaluate safety and tolerability of PPS over a 48‐week period.

Secondary and exploratory objectives include pain, function, and quality of life, pharmacokinetics, biomarkers, and inflammatory processes.

The study is being conducted at the Adelaide Women’s and Children’s Hospital with Dr David Ketteridge (Principal Investigator) and Dr Drago Bratkovic (Head of Metabolic Clinic). Three patients are currently enrolled and have completed the first 6 months of therapy.

Preliminary data from these three patients was presented in a poster at the International Congress of Inborn Errors of Metabolism (ICIEM) 2021. The data showed PPS was well tolerated out to 24 weeks of continuous dosing and there was an overall trend toward improvement in pain, function, activities of daily living and quality of life.

Paradigm is interested in exploring strategic partnerships to progress clinical studies to further evaluate PPS as a treatment to address the critical unmet need of ongoing musculoskeletal symptoms in this very rare patient population.

Mucopolysaccharidosis I

MPS I

Mucopolysaccharidosis Type I (MPS I), also known as Hurler (severe MPS I), Scheie, and Hurler-Scheie (attenuated / less severe MPS I) syndrome is part of a group of rare lysosomal storage diseases (LSD) caused by reduced levels, or the complete lack of, an enzyme responsible for the catabolism (break down) of glycosaminoglycans (GAGs) and resulting in the progressive accumulation of GAGs in the tissue. 1

GAG accumulation has a direct effect on connective tissue formation and function, causing progressive cellular damage affecting multiple organ systems and can lead to organ failure, cognitive impairment and reduced life expectancy.1

People with severe MPS I typically have an earlier onset of symptoms, a decline in intellectual function, and without treatment individuals with severe MPS I typically die before 10 years of age.1

Attenuated MPS I typically has a later onset of symptoms, milder symptoms and slower disease progression. While individuals with attenuated MPS I may develop significant disease-related morbidity, they typically show normal intelligence and may survive into adulthood.1

Heart disease and airway obstruction are major causes of death in all people with MPS I.2

Current standard of care for MPS includes haematopoietic stem cell transplantation (HSCT) and/or disease modifying enzyme replacement therapy (ERT), or supportive medical and surgical interventions.3

Despite available therapies people with MPS diseases continue to experience bone and joint manifestations, chronic pain, and physical disability, which generally persist despite treatment with HSCT and ERT.3

MPS I is present in about 1 in every 100,000 live births.4

Mucopolysaccharidosis I

MPS I

Mucopolysaccharidosis Type I (MPS I), also known as Hurler (severe MPS I), Scheie, and Hurler-Scheie (attenuated / less severe MPS I) syndrome is part of a group of rare lysosomal storage diseases (LSD) caused by reduced levels, or the complete lack of, an enzyme responsible for the catabolism (break down) of glycosaminoglycans (GAGs) and resulting in the progressive accumulation of GAGs in the tissue. 1

GAG accumulation has a direct effect on connective tissue formation and function, causing progressive cellular damage affecting multiple organ systems and can lead to organ failure, cognitive impairment and reduced life expectancy.1

People with severe MPS I typically have an earlier onset of symptoms, a decline in intellectual function, and without treatment individuals with severe MPS I typically die before 10 years of age.1

Attenuated MPS I typically has a later onset of symptoms, milder symptoms and slower disease progression. While individuals with attenuated MPS I may develop significant disease-related morbidity, they typically show normal intelligence and may survive into adulthood.1

Heart disease and airway obstruction are major causes of death in all people with MPS I.2

Current standard of care for MPS includes haematopoietic stem cell transplantation (HSCT) and/or disease modifying enzyme replacement therapy (ERT), or supportive medical and surgical interventions.3

Despite available therapies people with MPS diseases continue to experience bone and joint manifestations, chronic pain, and physical disability, which generally persist despite treatment with HSCT and ERT.3

MPS I is present in about 1 in every 100,000 live births.4

Key MPS I Figures

Incidence of live births4
1/100K
Expected lifespan with severe form, untreated1
10 YRS
Expected lifespan with attenuated form1
50 YRS
Market size (USD/pa) by 20275
$828M+

Key MPS I Figures

Incidence of live births4
1/100K
Expected lifespan with severe form, untreated1
10 YRS
Expected lifespan with attenuated form1
50 YRS
Market size (USD/pa) by 20275
$828M+

Drug in development

Pentosan
Polysulfate
Sodium

for subcutaneous injection

Potential

There is an unmet need to help manage bone and joint manifestations, chronic pain, and physical disability, key clinical manifestations of MPS I which remain despite treatment with HSCT and ERT.3
PPS has been shown to reduce GAG levels, inflammatory biomarkers, joint stiffness, and pain in preclinical MPS models and in clinical trials in MPS patients.6-10

The mechanisms of action of PPS that are relevant to the treatment of MPS include:

- Reduction in systemic and accumulated GAGs in multiple tissues11
- Anti-inflammatory effects via the inhibition of NF-kB resulting in the reduction in pro-inflammatory mediators12
- Reduction of the expression of the pain mediator, nerve growth factor (NGF) in osteocytes from degenerating joints 13
- An ability to inhibit the cartilage degrading enzymes that are related to joint dysfunction observed in MPS14

Remodelling
Inflammation
Pain
Cartilage Loss

Development milestones

In 2018, Paradigm entered into an exclusive license agreement for the use of PPS to treat lysosomal storage diseases (LSDs) including MPS (MPS types I, II, III, IV, VI and VII), Gaucher and Fabry diseases. The licensing agreement is a valuable addition to Paradigm’s product pipelines and IP portfolio. Granted patents cover key regions such as USA, Japan, Europe, Australia and New Zealand.

In addition, Paradigm has an exclusive supply and license agreement with the only FDA approved PPS supplier, bene pharmaChem, extending for 25 years post registration.

Paradigm’s current focus is on MPS Types I and VI, where there is an unmet medical need to manage residual musculoskeletal and pain symptoms.

Paradigm has received Orphan Designations in both the USA and EU for MPS Types I and VI. These designations allow for faster processing times for clinical trials in these regions, more regulatory support from the EMA, and for longer market exclusivity periods in the US and EU.

Considering the encouraging results of PPS effect on pain, function and biomarkers seen in animals and clinical studies reported to date, and the support of global leaders in MPS, Paradigm has commenced a clinical program assessing subcutaneous (SC) injections of PPS in MPS I.

In 2020 Paradigm commenced an open‐label single‐centre pilot study in up to 10 patients assessing SC injections of PPS in participants with MPS I who have received ERT and/or HSCT. (PARA_MPSI_001)

The primary objective of the study is to evaluate safety and tolerability of PPS over a 48‐week period.

Secondary and exploratory objectives include pain, function, and quality of life, pharmacokinetics, biomarkers, and inflammatory processes.

The study is being conducted at the Adelaide Women’s and Children’s Hospital with Dr David Ketteridge (Principal Investigator) and Dr Drago Bratkovic (Head of Metabolic Clinic). Three patients are currently enrolled and have completed the first 6 months of therapy.

Preliminary data from these three patients was presented in a poster at the International Congress of Inborn Errors of Metabolism (ICIEM) 2021. The data showed PPS was well tolerated out to 24 weeks of continuous dosing and there was an overall trend toward improvement in pain, function, activities of daily living and quality of life.

Paradigm is interested in exploring strategic partnerships to progress clinical studies to further evaluate PPS as a treatment to address the critical unmet need of ongoing musculoskeletal symptoms in this very rare patient population.